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T cell differentiation in chronic infections

Failure to clear an infection coincides with the appearance of T cells expressing low levels of cytokines and effector molecules and with the expression of inhibitory receptors such as PD-1, Lag-3, or Tim-3. T cells with this phenotype have so far been considered as terminally differentiated and exhausted effector T cells.

We recently found that T cells with memory-like properties are generated during chronic infection. When populations of T cells with an exhausted phenotype are transferred into naïve recipients and the hosts are subsequently re-challenged with a pathogen causing an acute infection, we noted a significant residual proliferative capacity within the transferred virus-specific T cell population, while we could exclude that the re-expansion potential relies on activating recent thymic emigrants (Utzschneider and Zehn, Nature immunology 2013). Furthermore, the re-expanding T cells obtained from chronic infection acquired memory-like properties in terms of being able to eliminate a secondary acute viral infection. Most interestingly, a large fraction of re-expanding T cells retained in the secondary acute infection the phenotype and cytokine profile which they acquired during chronic infection (Utzschneider and Zehn, Nature immunology 2013).

Therefore, we conclude that T cells undergo in chronic infections a form of differentiation that is stably passed on to daughter cells. We consider that T cells exhaustion could represents a specific and heritable differentiation state that could reflect an adjustment of T cells to the particular condition of persisting infections rather than primarily T cell senescence.

The re-expansion of functional T cells from chronic infections raises several questions. i) What characterizes cells that retain re-expansion potential in chronic infection, ii) is there a permanent or a temporary gain of function, iii) which molecules are differentially expressed in re-expanded and exhausted T cells, 4i) and, in light of our recent findings, does exhaustion exists or is it only a form of T cell differentiation occuring in chronic infections. Several ongoing projects aim to address these and related questions.

Selected publications
  • Utzschneider D.T., Legat A., Fuertes Marraco S.A., Carrié L., Luescher I., Speiser D.E. and Zehn D. T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. Nat. Immunol. 2013, 14:603-610. PubMed

  • Legat A., Speiser D.E., Pircher H., Zehn D. and Fuertes Marraco S.A. Inhibitory Receptor Expression Depends More Dominantly on Differentiation and Activation than "Exhaustion" of Human CD8 T Cells. Front. Immunol. 2013, 4:455. PubMed